The purpose this proposal is to investigate whether Epstein-Barr virus (EBV) and human T cell leukemia virus (HTLV) play a role in the etiology of AIDS. EBV and HTLV, both transforming viruses, have been implicated in immune suppression and lymphomas. Our recent results suggest that both EBV and HTLV are cytopathic in cells which are normally not susceptible to these viruses because of an active anti-viral immune response or host cell restrictions. We thus postulate that individuals at high risk of AIDS develop virulent host cell range variants of EBV, HTLV, or other transmittale DNA- or RNA-core viruses, which are no longer susceptible to the existing controls of initial infection and spreading. The result is degeneration of thymic epithelium, elimination of helper T lymphocytes, and immunodeficiency. The above hypothesis will be evaluated by following two experimental trails suggested in this RFA: 1) In vitro search for direct morphological transformation and/or cytopathology of appropriate EBV and HTLV target cells presumably involved in immunodeficiency (pre-B cells, suppressor and helper T lymphocytes, thymic epithelial cells, etc.). The studies will include: screening of cells from various tissues for virus binding, penetration, integration and expression of viral genomes. Synthesis of the virus-determined proteins will be followed by immunofluorescence, immunoblotting, radioimmunoprecipitation; 2) Analysis of tissue from healthy individuals, persons at risk of AIDS, and AIDS patients, for the presence, state of integration, and location of viral or pro-viral DNA, in particular in the potential EBV and HTLV target cells as determined in studies proposed above. We will use molecular EBV DNA and HTLV cDNA prepared in our laboratory, and the following tests: nucleic acid hybridization in situ and on filters, and Southern blot analysis. If EBV, HTLV, their new isolates, or other unknown virus eventually prove to be the cause of AIDS, a specific test for the early diagnosis of the condition may be feasible. Assays for the transmittable agent in blood can be designed. Ultimately, a vaccine protecting high risk individuals may be developed.